ABSTRACT The limited and dwindling effectiveness of current anti-malaria drugs creates an urgent medical need to identify new anti-malarials with novel protein targets. While potentially useful liver- and blood-stage inhibitors of malaria have been identified in phenotypic cell- based screening efforts, a major hurdle in the development of these newly discovered inhibitors is the elucidation of their mode of action. The proposed research involves the use of proteome-wide measurements of protein folding and stability to identify the protein targets of two liver- and blood-stage inhibitors of malaria parasites including clemastine fumarate and concanamycin A. The anti-malarial activities of the two compounds to be investigated here were recently discovered in cell-based screens. While the liver- and blood-stage IC50 values of these compounds have been evaluated in cell-based assays, the protein targets responsible for their anti-malarial activities are not known. Identifying the molecular target(s) of the active compounds discovered through phenotypic screening is an important but challenging task. Proposed here is the use of two different energetic-based methods, the Stability of Proteins from Rates of Oxidation (SPROX) technique and the Cellular Thermal Shift Assay (CETSA) to identify Plasmodium falciparum protein targets in parasite lysates, both direct and indirect, of clemastine fumarate and concanamycin A. Selected protein hits identified using these energetics-based techniques will be overexpressed in E. Coli and then the proteins in the unpurified E. Coli cell lysates will be re-analyzed by the SPROX and/or CETSA techniques using targeted proteomics methods to differentiate those protein hits that result from direct versus indirect binding interactions with the two anti-malarial agents studied here.